FDA to Review BLA for Perioperative Pembrolizumab/Chemotherapy for Stage II-IIIB NSCLC


With statistically significant and clinically meaningful event-free survival improvement in patients with stage II-IIIB Non–small cell lung cancer, could perioperative pembrolizumab in combination with chemotherapy become a new treatment option?

The FDA has accepted a biologics license application for pembrolizumab (Keytruda) for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) non–small cell lung cancer (NSCLC) in combination with platinum containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment.1

The application is supported by findings from the phase 3 KEYNOTE-671 clinical trial (NCT03425643), which has met its primary end point by showing a statistically significant and clinically meaningful improvement in event-free survival (EFS). The Prescription Drug User Fee Act target action data has been set to October 16, 2023.

“Results from KEYNOTE-671 show that [pembrolizumab] in combination with chemotherapy provided significant improvement in event-free survival, pathological complete response and major pathological response over chemotherapy alone as a perioperative treatment regimen for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer,” said Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “

According to interim analysis results evaluated by an independent Data Monitoring Committee, KEYNOTE-671 has demonstrated statistically significant improvements in pathological complete response (pCR) and major pathological response (mPR), 2 key secondary end points of KEYNOTE-671. Additional findings from the study will be an upcoming medical meeting.

In the randomized, double-blind KEYNOTE-671 study, 786 patients will be enrolled and randomized 1:1 to receive either a perioperative pembrolizumab combination or placebo in combination with chemotherapy. These patients will be assessed for the coprimary end points of EFS and overall survival, as well as the secondary end points of mPR, pCR, quality of life, adverse events (AEs), perioperative complications, and treatment discontinuation as a result of AEs.1,2

"EFS, I believe, is a valid endpoint for these patients, going along with other studies approaches of landmarks other than OS. It supports the class effect of preoperative immunotherapy, but does not answer the question is just a neoadjuvant approach enough or do we need the adjuvant immunotherapy as well as done here. This is important not only from a toxicity perspective, but also from a societal perspective given the costs of these drugs, and will likely be debated endlessly, looking at secondary endpoints and tails-on-the-curve in the absence of randomized data. It joins adjuvant atezoliziumab from IMpower010 [NCT02486718] and the previous findings of only adjuvant pembrolizumab from KEYNOTE 091 [NCT02504372] in this space, and we expect other studies to soon follow as well with other checkpoint inhibitors," Alexander I. Spira, MD, PhD, FACP, medical oncologist at Virginia Cancer Specialists, co-director, VCS Research Institute, director, Thoracic and Phase I Program, and clinical assistant professor, Johns Hopkins told Targeted OncologyTM.

In the perioperative pembrolizumab arm, patients will be administered pembrolizumab 200 mg intravenously (IV) every 3 weeks [Q3W] for up to 4 cycles plus cisplatin 75 mg/m2, IV on day 1 of each cycle, and either gemcitabine 1000 mg/m2, IV on days 1 and 8 of each cycle, or pemetrexed 500 mg/m2, IV on day 1 of each cycle. Treatment in this arm will be given as neoadjuvant therapy prior to surgery, followed by pembrolizumab 200 mg IV Q3W for up to 13 cycles as adjuvant therapy post-surgery. In the control arm, patients will receive matching placebo plus chemotherapy.

Patients are eligible for KEYNOTE-671 if that have previously untreated and pathologically confirmed stage II, IIIA, or IIIB NSCLC, available tumor tissue for PD-L1 testing, an ECOG performance status of 0 or 1, and adequate organ function.2

Patients with stage II-IIIB NSCLC are excluded from the study if their tumor location involves the superior sulcus, large cell neuro-endocrine cancer, or sarcomatoid tumor. Other ineligible patients include those history of pneumonitis/interstitial lung disease, hypersensitivity or pembrolizumab or other study drugs, Hepatitis B or C, active tuberculosis, current immunodeficiency, or an additional malignancy within the past 5 year. Patients are also excluded if they received prior systemic anti-cancer therapy involving investigational agents, prior radiotherapy within 2 weeks of study treated, or a live vaccine within 30 days of the first dose of study treatment.

"By moving this [pembrolizumab]-based regimen into earlier stages of non-small cell lung cancer, we may be able to significantly reduce the risk of recurrence for these patients. This study is an important milestone, and we look forward to sharing the detailed results with the medical community as soon as possible. We thank the patients and investigators for their important contributions to this study," said Barr, in the press release.


1. Merck announces phase 3 KEYNOTE-671 trial met primary endpoint of event-free survival (EFS) in patients with resectable stage II, IIIA or IIIB non-small cell lung cancer. News release. Merck. March 1, 2023. Accessed March 1, 2023. https://bit.ly/3ZptHwu

2. Efficacy and safety of pembrolizumab (MK-3475) with platinum doublet chemotherapy as neoadjuvant/adjuvant therapy for participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (MK-3475-671/KEYNOTE-671). ClinicalTrials.gov. Updated August 19, 2022. Accessed March 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03425643?term=KEYNOTE-671&draw=2&rank=1

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